Submissions for variant NM_006019.4(TCIRG1):c.303_309del (p.Glu102fs)

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Minimum conflict level: Report conflict between different conditions
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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000672867	SCV000373698	uncertain significance	Autosomal recessive osteopetrosis 1	2017-04-27	criteria provided, single submitter	clinical testing	The TCIRG1 c.303_309delGGAGCGC (p.Glu102TrpfsTer62) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for osteopetrosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl	RCV000672867	SCV000798015	likely pathogenic	Autosomal recessive osteopetrosis 1	2018-02-20	criteria provided, single submitter	clinical testing
Invitae	RCV001850622	SCV002243163	pathogenic	not provided	2021-03-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with TCIRG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 305784). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Glu102Trpfs*62) in the TCIRG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TCIRG1 are known to be pathogenic (PMID: 10888887, 10942435, 11532986, 19448635).

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